Zeng, 2014

https://pubmed.ncbi.nlm.nih.gov/25428396/

• Background: Despite several studies investigating the association between the human leukocyte antigen HLA-B*1502 allele and lamotrigine-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in Han Chinese subjects, the relationship remains unclear.

•  Results: Four studies including a total of 12 patients with SJS/TEN and 128 lamotrigine-tolerant control subjects were identified. The HLA-B*1502 allele was present in 33.3% (four of 12) of lamotrigine-induced SJS/TEN cases but in only 9.4% (12 of 128) of lamotrigine-tolerant controls. The occurrence of SJS/TEN was thus associated with the presence of the HLA-B*1502 allele (odds ratio: 4.98, 95% confidence interval 1.43-17.28; P < 0.05). 

Bloch, 2014

https://pubmed.ncbi.nlm.nih.gov/24897291/

• Antiepileptic drugs can induce potentially life-threatening hypersensitivity reactions such as Stevens-Johnson syndrome at a frequency of one in 10,000 to one in 1000 treated patients. There is a considerable cross-reactivity among different antiepileptic drugs but the mechanisms are not known. 

• In this review we have summarized current evidence on antiepileptic drug-induced hypersensitivity reactions and performed meta-analyses of published case-control studies that investigated associations between HLA alleles and several antiepileptic drugs in diverse populations. 

• As the heterogeneity between studies was high, we conducted subsequent subgroup analyses and showed that HLA-B*15:02 was associated with carbamazepine, lamotrigine and phenytoin-induced Stevens-Johnson syndrome in Asian populations indicating that pretreatment testing may prevent cross-reactivity. Additionally, we explored the potential of new, high-throughput technologies that may help to understand the mechanisms and predict the risk of adverse drug reactions in the future.

• Keywords: HLA; antiepileptic drugs; carbamazepine; hypersensitivity reactions; lamotrigine; oxcarbazepine; pharmacogenetics; phenytoin.

Park, 2015

https://pubmed.ncbi.nlm.nih.gov/25327504/

• Purpose: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but fatal adverse mucocutaneous reactions to certain drugs. Recent studies suggest that ethnicity and genetic predisposition may play a crucial role in the manifestation of the reaction. In this study, we described the role of human leukocyte antigen (HLA)-B alleles in the development of clinical characteristics and treatment outcomes of SJS/TEN in a single Korean tertiary hospital.

• Methods: We retrospectively reviewed the medical records (from March 1, 2010 to February 28, 2014) of 30 patients diagnosed with SJS and/or TEN.

• Results: The main causative drugs were anticonvulsants (26.7 %) and allopurinol (26.7 %), followed by antibiotics (16.7 %), acetazolamide (10.0 %), acetaminophen (10.0 %), and herbal medication (6.7 %). The mean latencies of these drugs were variable. Liver damage was the most common symptom (observed in 63.3 % of the patients). Of the five patients with lamotrigine-induced SJS/TEN, three expressed the HLA-B*4403 allele (60.0 %). Of the seven patients with allopurinol-induced SJS/TEN, five expressed the HLA-B*5801 allele (71.4 %).

• Conclusions: The major SJS/TEN-inducing drugs were found to be allopurinol and anticonvulsants (such as lamotrigine). We speculated that Korean individuals expressing the HLA-B*4403 allele may be highly susceptible to lamotrigine-induced SJS/TEN.

Park, 2016

https://pubmed.ncbi.nlm.nih.gov/26632391/

Abstract

• Purpose: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are very serious forms of drug-induced cutaneous adverse reaction. SJS/TEN induced by certain drug is well known to be associated with some human leukocyte antigen (HLA) gene type. We aimed to explore HLA allele frequencies and their association with SJS/TEN according to culprit drugs in Korea.

• Materials and methods: We enrolled 5802 subjects who had results of HLA typing test from August 2005 to July 2014. Total 28 SJS/TEN patients were categorized based on culprit drugs (allopurinol, lamotrigine, carbamazepine) and identified the presence of HLA-B*58:01, HLA-B*44:03, HLA-B*15:02, and HLA-A*31:01.

• Results: HLA-A*24:02 (20.5%), HLA-B*44:03 (10.0%), and HLA-Cw*01:02 (17.1%) were the most frequent type in HLA-A, -B, and -C genes, respectively. Allele frequencies of HLA-B*58:01, HLA-B*44:03, HLA-A*31:01, and HLA-B*15:02 were 7.0%, 10.0%, 5.0%, and 0.3%, respectively. In 958 allopurinol users, 9 subjects (0.9%) were diagnosed with SJS/TEN. Among them, 8 subjects possessed HLA-B*58:01 allele. SJS/TEN induced by allopurinol was more frequently developed in subjects with HLA-B*58:01 than in subjects without it [odds ratio: 57.4; confidence interval (CI) 7.12-463.50; p<0.001]. Allopurinol treatment, based on screening by HLA-B*58:01 genotyping, could be more cost-effective than that not based on screening. HLA-B*44:03 may be associated with lamotrigine-induced SJS/TEN (odds ratio: 12.75; CI 1.03-157.14; p=0.053). Among carbamazepine users, only two patients experienced SJS/TEN and possessed neither HLA-B*15:02 nor HLA-A*31:03.

• Conclusion: HLA gene frequencies varied in Korea. Screening of HLA-B*58:01 before the use of allopurinol might be needed to anticipate probability of SJS/TEN.

  Deng, 2018https://pubmed.ncbi.nlm.nih.gov/30015149/Fricke-Galindo,
 

• Purpose: The aim of this study was to assess the association between human leukocyte antigen (HLA) variants and lamotrigine (LTG)-induced cutaneous adverse drug reactions (cARDs).
• Methods: A comprehensive literature search was conducted on the relationship of HLA alleles with LTG-induced cADRs in Asian populations, through PubMed, Embase, and Cochrane Library. The last search was in February 2018. The pooled odds ratio (OR) with 95% confidence interval (95% CI) was used to access the strength of the association between an HLA allele and LTG-induced cADRs.
• Results: A total of 11 studies met the inclusion criteria and were enrolled in our meta- analysis, which were based on Chinese, Korean, and Thai populations. Among these populations, we observed that HLA-B*1502 is a risk allele for LTG-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in Chinese populations (pooled OR 2.4, 95% CI: 1.20-4.78, P = 0.01), HLA-A*2402 was found to be a significant risk allele for both SJS/TEN (pooled OR 3.50, 95% CI: 1.61-7.59, P = 0.002) and maculopapular eruption (MPE) (pooled OR 2.14, 95% CI: 1.10-4.16, P = 0.03), and HLA-B*3303 was considered to be a protective marker for MPE in Chinese and Korean populations (pooled OR 0.2, 95% CI 0.06-0.64, P = 0.007).
• Conclusions: In Asian populations, HLA-B*1502 is a risk factor for LTG-induced bullous lesions such as SJS/TEN in Chinese populations, and HLA-A*2402 is associated with the susceptibility to either SJS/TEN or MPE. HLA-A*3303 is a protective allele against LTG-induced MPE in Chinese and Korean populations.

Sukasem, 2014https://pubmed.ncbi.nlm.nih.gov/25495410/  

• Aim: Several HLA alleles have been associated with antiepileptic drugs (AEDs)-induced cutaneous adverse drug reactions (cADRs) in different populations; however, this has not been investigated in Mexican Mestizos (MM). Thus, the purpose of this preliminary study was to determine the association of HLA class I alleles with AED-induced cADRs in MM patients.
• Materials & methods: This case-control association study included 21 MM patients with phenytoin (PHT)-, carbamazepine (CBZ)-, or lamotrigine (LTG)-induced maculopapular exanthema (MPE) or Stevens-Johnson syndrome (SJS); 31 MM patients tolerant to the same AEDs; and 225 unrelated, healthy MM volunteers. HLA class I genotyping was performed. Differences in HLA allele frequencies between AED-induced cADR patients and AED-tolerant patients were assessed. Frequencies of alleles possibly associated with AED-induced cADRs in MM patients were compared with those in MM population.
• Results: The frequency of HLA-C*08:01 allele in PHT-induced MPE was higher than that in the PHT-tolerant group (pc=0.0179) or in the MM population (pc<0.0001). For the first time, HLA-A*02:01:01/-B*35:01:01/-C*04:01:01 haplotype was associated with LTG-induced MPE (pc=0.0048 for LTG-tolerant groups and pc<0.0001 for MM population).
• Conclusion: Our data suggest the HLA-A*02:01:01/-B*35:01:01/-C*04:01:01 haplotype may be a biomarker for LTG-induced MPE and the HLA-C*08:01 allele for PHT-induced MPE. We also identified HLA-A*01:01:01 and -A*31:01:02 as candidates alleles associated with CBZ-induced MPE in MM patients. However, further investigations are necessary to confirm these findings.

Kek Teh, ,2021

https://pubmed.ncbi.nlm.nih.gov/34175889/
 

• Aromatic antiepileptic drugs (AEDs)-induced cutaneous adverse drug reactions (cADRs) add up to the limited use of the AEDs in the treatment and prevention of seizures. Human leukocyte antigen-B (HLA-B) alleles have been linked to AEDs-induced cADRs.

•  We investigated the association between cADRs (including Stevens-Johnson syndrome; SJS/toxic epidermal necrolysis; TEN, drug reaction with eosinophilia and systemic symptoms; DRESS, and Maculopapular eruption; MPE) caused by AEDs (phenytoin, carbamazepine, lamotrigine, phenobarbital and oxcarbazepine) and HLA-B alleles in Thai population. 

• Through the case-control study, 166 patients with AEDs-induced cADRs, 426 AEDs-tolerant patients (AEDs-tolerant controls), and 470 healthy subjects (Thai population) were collected. The HLA genotypes were detected using the polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) method. 

• We also performed a meta-analysis with these data and other populations. The carrier rate of HLA-B*15:02 was significantly different between AEDs-induced cADRs group and AEDs-tolerant group (Odds ratio; OR 4.28, 95% Confidence interval; CI 2.64-6.95, p < 0.001), AEDs-induced cADRs group and Thai population (OR 2.15, 95%CI 1.41-3.29, p < 0.001). In meta-analysis showed the strong association HLA-B*15:02 with AEDs-induced cADRs (OR 4.77, 95%CI 1.79-12.73, p < 0.001). 

• Furthermore, HLA-B*15:02 was associated with SJS/TEN induced by AEDs (OR 10.28, 95%CI 6.50-16.28, p < 0.001) Phenytoin (OR 4.12, 95%CI 1.77-9.59, p = 0.001) and carbamazepine (OR 137.69, 95%CI 50.97-371.98, p < 0.001). 

• This study demonstrated that genetic association for AEDs-induced cADRs was phenotype-specific. A strong association between HLA-B*15:02 and AEDs-induced SJS/TEN was demonstrated with an OR of 10.79 (95%CI 5.50-21.16, p < 0.001) when compared with AEDs-tolerant group. 

• On the other hand, the carrier rates of HLA-B*08:01, HLA-B*13:01, and HLA-B*56:02 were significantly higher in the DRESS group compared with the AEDs-tolerant group (p = 0.029, 0.007, and 0.017, respectively). The HLA-B*15:02 allele may represent a risk factor for AEDs-induced cADRs.

• Purpose: The importance of HLA-B*15:02 genotyping to avoid carbamazepine induced SJS/TEN and molecular modeling to predict the role of HLA-B*15:0 and AEDs induced SJS/TEN are investigated.

• Methods: DNA was extracted from eighty-six patients. The patients were genotyped by AS-PCR. Computational modeling of the HLA-B*15:02 followed by docking studies were performed to screen 26 AEDs that may induce ADR among HLA-B*15:02 carriers.

• Results: Odd ratio for CBZ induced SJS/TEN and HLA-B*15:02 was 609.0 (95% CI: 23-15873; p=0.0002). Molecular modeling studies showed that acetazolamide, ethosuxiamide, lamotrigine, oxcarbazepine, phenobarbital, phenytoin, primidone and sodium-valproate may induce ADR in HLA-B*15:02 carriers alike CBZ. Conclusion. We confirmed HLA-B*15:02 as a predictor of SJS/TEN and recommend pre-screening. Computational prediction of DIHR is useful in personalized medicine.

•  Drug-induced skin injuries, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug-induced hypersensitivity syndrome (DIHS) are all reported LTG-related adverse events [130-138]. SJS/TEN in LTG-treated pediatric patients (n=486) was reported in many studies and 97% of cases occurred within 8 weeks of initiation of LTG therapy, with a median time to onset of 15 days [139]. 

• Human leukocyte antigen (HLA) genes produce proteins which identify foreign particles in the immune system [140]. The complex of drug antigen/metabolite-human leukocyte antigen (HLA)-T cell receptor (TCR) initiates immune reactions for SJS/TEN. Specific HLA alleles or variant predisposition and interaction with a drug allow the presentation of drug-bound HLA to the TCR, which further triggers the activation of CD8+ cytotoxic lymphocytes and a series of specific immune reactions which ultimately cause keratinocyte apoptosis and severe drug-induced skin injuries [141-145]. 

• HLA-B genotypes and LTG-induced cutaneous adverse drug reaction (LTG-cADR) associations have been described in several reports. HLA-B*15:02 is associated with SJS in response to LTG administration in multiple populations [18-23]. 

• Another study reported that HLA-B*38:01 was significantly associated with LTG-related SJS/TEN in a Spanish Caucasian population (p<0.001) [146]. HLA-DRB1*04:05 and HLA-DQB1*04:01 alleles occurred in a higher frequency in Japanese patients with LTG-cADRs. These two alleles are in linkage disequilibrium in this population, along with HLA-DQA1*03:03, which is also associated with LTG-cADRs [147]. 

• Purpose: Aromatic antiepileptic drugs (AEDs) are frequently implicated in cutaneous adverse drug reactions (cADRs), a few of which are associated with certain human leukocyte antigen (HLA) alleles in some populations. We aimed to find HLA-associations with AED-related cADRs among North Indians.

• Methods: North Indian subjects with cADR due to an AED, and those who were AED-tolerant were recruited as cases and controls, respectively. Genotyping for HLA-A, B and DRB1 were performed. Statistical analysis to compare carrier-rates and allele-frequencies between cases and controls (and healthy population, where necessary), was done for HLA-alleles occurring more than twice in either group.

• Results: 120 cases {11 - Lamotrigine (LTG), 14 -Valproic acid (VPA), 8 -Levetiracetam (LEV), 35 -Carbamazepine (CBZ) and 52 - Phenytoin (PHT)}, and 250 controls were recruited. Presence of HLA-A*31:01 and HLA-B*51:01 were found to increase the risk of Maculopapular exanthema (MPE) due to CBZ and PHT (OR = 6.38; 95% CI: 1.46-27.75; OR = 4.60; 95% CI: 1.54-13.72, respectively). 

• Among the severe cADRs, HLA-B*57:01(OR = 11.00 95% CI: 1.41-85.81) and HLA-DRB1*07:01 (OR = 7.25; 95% CI: 1.09-48.18) were noted to be significantly associated with CBZ-induced Stevens Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN); HLA-B *51:01 was associated with drug reaction eosinophilia and systemic symptoms (DRESS) caused by PHT (OR = 6.90; 95% CI: 1.38-34.29).

• Conclusions: We found significant associations of some HLA alleles with specific cADRs to CBZ and PHT in North Indians, which may need to be tested before AED-initiation; only screening for HLA-B*15:02 may not help in this population.

• In this case-control study, class І and ІІ human leukocyte antigen (HLA) alleles in Iranian patients with benign and severe cutaneous adverse drug reactions (CADRs) due to aromatic anticonvulsants and antibiotics were evaluated. Patients diagnosed with CADRs (based on clinical and laboratory findings) with a Naranjo score of ≥ 4 underwent blood sampling and HLA-DNA typing. The control group comprised 90 healthy Iranian adults. Alleles with a frequency of more than two were reported. Deviations from Hardy-Weinberg equilibrium were not observed. Eighty patients with CADRs including 54 females and 26 males with a mean age of 41.49 ± 16.08 years were enrolled in this study. The culprit drugs included anticonvulsants (lamotrigine, carbamazepine, and phenytoin) and antibiotics (ciprofloxacin and co-trimoxazole). The comparison of allele frequencies in the Iranian healthy control group and the group with benign CADRs revealed that HLA-Cw*04, and HLA-A*24 were significantly associated with lamotrigine-induced maculopapular CADRs. Furthermore, HLA-B*51 showed a significant correlation with carbamazepine-induced maculopapular CADRs. 

• Significant associations were also detected between ciprofloxacin-induced urticarial CADRs with HLA-B*40, and HLA-DRB1*14. In the severe group, HLA-B*38 and HLA-DRB1*13 were significantly associated with lamotrigine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). 

• Moreover, HLA-A*31 and HLA-Cw*04 were significantly correlated with carbamazepine-induced drug reactions with eosinophilia and systemic symptoms (DRESS). HLA-B*08 also showed a significant correlation with ciprofloxacin-induced acute generalized exanthematous pustulosis (AGEP). 

• In conclusion, Lamotrigine-induced MPE was significantly correlated with HLA-Cw*04, and HLA-A*24. Similarly, lamotrigine-induced SJS/TEN was significantly associated with HLA-B*38 and HLA-DRB1*13. Additionally, HLA-A*31 was associated with DRESS caused by carbamazepine. The most frequent CADR-inducing drugs were anticonvulsants.
• 
  

 X Li, 2014

https://pubmed.ncbi.nlm.nih.gov/24871931/

• Background and study aims: Stevens-Johnson syndrome (SJS) and  toxic epidermal necrolysis (TEN) are fatal adverse cutaneous drug reactions which may be induced by phenytoin (PHT) or lamotrigine (LTG). The objective of this study was to analyze the association of human leukocyte antigen (HLA)-B*1502 and PHT or LTG induced SJS/TEN.

• Patients and methods: All the participants were epileptic patients and the SJS/TEN were induced by PHT or LTG. The presence or absence of the HLA-B*1502 allele of all the patients was determined. ISI Web of Knowledge, PubMed, ScienceDirect, EMBASE, and Cochrane Register of Controlled Trials (CENTRAL) data were searched for the literature published before April 2014. Meta-analysis was performed using Review Manager 5.2 software.

• Results: From 256 citations, 6 English studies were included that involved 480 epilepsy patients. Meta-analysis showed that odd ratio (OR) of PHT and LTG were 5.65 [95% CI: 2.76-11.57] and 4.51 [95% CI: 1.57-12.98], respectively. Funnel plot analysis showed symmetry, indicting less possible publication bias and the results were partly reliable.

• Conclusion: There is a significant association between HLA-B*1502 and PHT or LTG-induced SJS/TEN.

Moon, 2015

https://pubmed.ncbi.nlm.nih.gov/26282450/

• The use of lamotrigine (LTG) can be limited by the occurrence of cutaneous adverse drug reactions (cADRs) that range from maculopapular eruption (MPE) to the more severe Stevens-Johnson syndrome and toxic epidermal necrolysis. A few human leukocyte antigen (HLA)-related genetic risk factors for carbamazepine-induced cADR have been identified. 

• However, the HLA-related genetic risk factors associated with LTG-induced cADR are not yet well known. We performed HLA genotyping in 50 Korean patients with epilepsy, including 21 patients presenting LTG-induced MPE and 29 LTG-tolerant patients. A significant association between the HLA-A*2402 allele and LTG-induced MPE was identified, in comparison with the LTG-tolerant group (odds ratio [OR] 4.09, p = 0.025) and the general Korean population (OR 3.949, p = 0.005). The frequencies of the Cw*0102 or Cw*0702 alleles were significantly higher in the LTG-MPE group than in the Korean population, whereas the frequency of the A*3303 allele was lower. 

• The coexistence of the A*2402 and Cw*0102 alleles was significantly associated with the LTG-MPE group when compared to the LTG-tolerant group (OR 7.88, p = 0.007). 

• In addition, the Cw*0701 allele was more frequent in the LTG-tolerant group than in the Korean population. These findings suggest the presence of HLA-related genetic risk factors for LTG-induced MPE in the Korean population
  

Koomdee, 2014

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127646/

Background:  Lamotrigine is a commonly used in psychiatric patients. The aims of this study were to determine the possible associations of lamotrigine-induced hypersensitivity syndrome with the HLA-B alleles in Thai patients. HLA-B*58:01 allele was also observed in Han Chinese patients with epilepsy and lamotrigine-induced SCARs (severe cutaneous adverse drug reactions).

• Method:  A total of 133 patients, including 11 patients with lamotrigine-induced hypersensitivity syndrome (MPE; maculo-papular exanthema, SJS; Stevens-Johnson syndrome and TEN; toxic epidermal necrolysis), 9 lamotrigine-tolerant controls and 113 healthy controls were included in this study. HLA-B genotyping was performed. This case-control study was approved by the Ethics Committee of Ramathibodi Hospital.

• Results:  HLA-B*15:02 allele was present in 27.3% (3/11) of Thai patients with lamotrigine-induced hypersensitivity syndrome but in only 11.1% (1/9) of lamotrigine-tolerant controls and 13.2% of 113 healthy controls (P-value <0.05). Other HLA-B allele, including HLA-B*58:01 was observed in a case group.

• Conclusion:  Our results support the hypothesis that HLA-B*15:02 contribute to the genetic susceptibility to lamotrigine-induced hypersensitivity syndrome and may be valuable as potential biomarkers for prediction lamotrigine-induced hypersensitivity syndrome in Thai population. A major limitation of this study was the size of the sample available for the analysis. Confirmation of these results in a larger, independent sample is needed.

X Li, 2015

https://pubmed.ncbi.nlm.nih.gov/24871931/

• Background and study aims: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are fatal adverse cutaneous drug reactions which may be induced by phenytoin (PHT) or lamotrigine (LTG). The objective of this study was to analyze the association of human leukocyte antigen (HLA)-B*1502 and PHT or LTG induced SJS/TEN.

• Patients and methods: All the participants were epileptic patients and the SJS/TEN were induced by PHT or LTG. The presence or absence of the HLA-B*1502 allele of all the patients was determined. ISI Web of Knowledge, PubMed, ScienceDirect, EMBASE, and Cochrane Register of Controlled Trials (CENTRAL) data were searched for the literature published before April 2014. Meta-analysis was performed using Review Manager 5.2 software.

• Results: From 256 citations, 6 English studies were included that involved 480 epilepsy patients. Meta-analysis showed that odd ratio (OR) of PHT and LTG were 5.65 [95% CI: 2.76-11.57] and 4.51 [95% CI: 1.57-12.98], respectively. Funnel plot analysis showed symmetry, indicting less possible publication bias and the results were partly reliable.

• Conclusion: There is a significant association between HLA-B*1502 and PHT or LTG-induced SJS/TEN.
   

 
Ramírez, 2016/17

https://pubmed.ncbi.nlm.nih.gov/27888155/

• Aromatic antiepileptic drugs (AEDs) are among the drugs most frequently involved in severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS). This study investigated the associations between the genetic polymorphisms of HLA class-I and AED-induced SCARs in the Spanish population. HLA class-I genotypes were determined in AED (phenytoin[PHT], lamotrigine[LTG], carbamazepine[CBZ], phenobarbital[PB])-induced SJS/TEN (n=15) or DRESS (n=12) cases included in the Spanish SCAR registry, PIELenRed. 

• There were 3 control groups: (A)tolerant to a single AED, (B)tolerant to any AED, and (C)Spanish population controls. For SJS/TEN, concomitant HLA-A*02:01/Cw15:02 alleles were significantly associated with PHT-cases compared to control groups B and C [(B)odds ratio(OR):14.75, p=0.009;(C)OR:27.50, p<0.001], and were close to significance with respect to control group A (p=0.060). 

• The genotype frequency of the HLA-B*38:01 was significantly associated with PHT-LTG-cases compared with the 3 groups of controls [(A)OR:12.86, p=0.012;(B)OR:13.81; p=0.002;(C)OR:14.35, p<0.001], and with LTG-cases [(A)OR:147.00, p=0.001;(B)OR:115.00, p<0.001;(C)OR:124.70, p<0.001]. 

• We found the HLA-B*15:02 allele in a Spanish Romani patient with a CBZ-case. The HLA-A*11:01 was significantly associated with CBZ-cases [(A)OR:63.89, p=0.002;(B)OR:36.33, p=0.005;(C)OR:28.29, p=0.007]. For DRESS, the HLA-A*24:02 genotype frequency was statistically significant in the PHT-LTG-cases [(A)OR:22.56, p=0.003;(B)OR:23.50. p=0.001; (C)OR:33.25, p<0.001], and in the LTG-cases [(A),OR:49.00, p=0.015;(B)OR:27.77, p=0.005; (C)OR:34.53, p=0.002]. 

• HLA-A*31:01 was significantly associated with the CBZ-cases [(A)OR:22.00, p=0.047;(B)OR:29.50, p=0.033;(C)OR:35.14, p=0.006]. 

• In conclusion, we identified several significant genetic risk factors for the first time in the Spanish Caucasian population: HLA-A*02:01/Cw*15:02 combination as a risk factor for PHT-induced SJS/TEN, HLA-B*38:01 for LTG- and PHT- induced SJS/TEN, HLA-A*11:01 for CBZ-induced SJS/TEN, and HLA-A*24:02 for LTG- and PHT- induced DRESS. 

• The strong association between HLA*31:01 and CBZ-DRESS in Europeans was confirmed in this study.

Shi, 2017

https://pubmed.ncbi.nlm.nih.gov/28476759/Wanshu

• Objective: To investigate the involvement of human leukocyte antigen (HLA) loci in aromatic antiepileptic drug-induced cutaneous adverse reactions.

• Methods: A case-control study was performed to detect HLA loci involved in aromatic antiepileptic drug-induced Stevens-Johnson syndrome in a southern Han Chinese population. Between January 1, 2006, and December 31, 2015, 91 cases of Stevens-Johnson syndrome induced by aromatic antiepileptic drugs and 322 matched drug-tolerant controls were enrolled from 8 centers. Important genotypes were replicated in cases with maculopapular eruption and in the meta-analyses of data from other populations. Sequence-based typing determined the HLA-A, HLA-B, HLA-C, and HLA-DRB1 genotypes.

• Results: HLA-B*15:02 was confirmed as strongly associated with carbamazepine-induced Stevens-Johnson syndrome (p = 5.63 × 10-15). In addition, HLA-A*24:02 was associated significantly with Stevens-Johnson syndrome induced by the aromatic antiepileptic drugs as a group (p = 1.02 × 10-5) and by individual drugs (carbamazepine p = 0.015, lamotrigine p = 0.005, phenytoin p = 0.027). Logistic regression analysis revealed a multiplicative interaction between HLA-B*15:02 and HLA-A*24:02. 

• Positivity for HLA-A*24:02 and/or HLA-B*15:02 showed a sensitivity of 72.5% and a specificity of 69.0%. The presence of HLA-A*24:02 in cases with maculopapular exanthema was also significantly higher than in controls (p = 0.023). Meta-analysis of data from Japan, Korea, Malaysia, Mexico, Norway, and China revealed a similar association.

• Conclusions: HLA-A*24:02 is a common genetic risk factor for cutaneous adverse reactions induced by aromatic antiepileptic drugs in the southern Han Chinese and possibly other ethnic populations. Pretreatment screening is recommended for people in southern China.

 Alfirevic, 2003

https://pubmed.ncbi.nlm.nih.gov/12580987/ 

Abstract

• Aims: To test the role of acetylator status, and to investigate the reported discrepancy between acetylator phenotype and genotype in HIV-positive patients with sulphamethoxazole (SMX) hypersensitivity.

• Methods: Forty HIV-positive patients (32 of whom were SMX-hypersensitive), and 26 healthy volunteers, were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, and phenotyped using dapsone (50 mg) as a probe, for acetylator status. Sequencing of the NAT2 exon was performed where discrepancy between phenotyping and genotyping was detected. Our results were also pooled with published studies addressing slow acetylator status in HIV-positive SMX-hypersensitive patients.

• Results: Slow acetylator genotype and phenotype frequencies did not differ between HIV-positive SMX-hypersensitive and nonhypersensitive patients, and healthy controls, which was further confirmed in a meta-analysis of published studies (pooled odds ratio 2.25, 95% confidence interval 0.45, 11.17). Discordance between phenotype and genotype was resolved in four of the subjects by sequencing of the whole NAT2 exon, which revealed rare mutations, leaving three (9%) HIV-positive SMX-hypersensitive patients and one (4%) healthy volunteer who continued to demonstrate the discordance.

• Conclusions: Slow acetylator phenotype or genotype is unlikely to predispose to SMX hypersensitivity in HIV-positive patients, although a minor role cannot be excluded. Phenotype-genotype discrepancies are partly due to nondetection of all rare alleles by PCR methodology, and can be circumvented by sequencing of the gene in patients showing a discrepancy.

 Lonjou, 2008

https://pubmed.ncbi.nlm.nih.gov/18192896/

• Background: Stevens-Johnson syndrome (SJS) and its severe form, toxic epidermal necrolysis (TEN), are rare but life-threatening cutaneous adverse reactions to drugs, especially to allopurinol, carbamazepine, lamotrigine, phenobarbital, phenytoine, sulfamethoxazole, oxicam and nevirapine. Recently, a strong association between carbamazepine and allopurinol induced SJS or TEN has been described with respectively, HLA-B*1502 and HLA-B*5801 in a Han Chinese population from Taiwan and other Asian countries.

• Objective: The objective is to further investigate the relationship between SJS/TEN and HLA-B in a large number of patients in a European population.

• Methods: HLA-B genotyping was performed on 150 patients included in a European study (RegiSCAR) of SJS and TEN. We focused on patients related to 'high-risk' drugs including: 31 cases related to allopurinol, 28 to sulfamethoxazole, 19 to lamotrigine and 14 to oxicam.

• Results: Sixty-one percent of 31 allopurinol-induced SJS/TEN patients carried the HLA-B*5801 allele and the figure was 55% for 27 patients of European ancestry [odds ratio=80 (34-187)], (P<10(-6)) as previously observed in Han Chinese. For other drugs, two rare alleles showed a weaker association with SJS/TEN in a limited number of patients: B*38 for sulfamethoxazole or lamotrigine-related patients, and B*73 for oxicam.

• Conclusion: At variance with prior results in Asia, this study shows that even when HLA-B alleles behave as strong risk factors, as for allopurinol, they are neither sufficient nor necessary to explain the disease. Further investigations are necessary to delineate the exact role of the HLA region in SJS/TEN, and to look for other associations in other regions of the genome.
   

 Sabourirad, 2020/21

https://pubmed.ncbi.nlm.nih.gov/33217035/ 

• Previous studies have found an association between HLA-B*1502 allele and lamotrigine-induced Stevens-Johnson syndrome (SJS)/ toxic epidermal necrosis (TEN) spectrum in Han Chinese populations. This study aims to investigate the association between HLA-B*1502 and lamotrigine- or phenytoin- induced SJS/TEN in an Iranian population. 

• The medical records of twenty-eight lamotrigine-induced SJS/TEN patients and twenty-five lamotrigine-tolerant controls as well as eight phenytoin-induced SJS/TEN and twelve phenytoin-tolerant controls were extracted between March 2013 and March 2019 from the university hospitals in Mashhad, Iran. 

• The presence of HLA-B*1502 allele was determined using real-time polymerase chain reaction (PCR). Among lamotrigine-induced patients with SJS/TEN, 11 (39.3%) patients tested positive for the HLA-B*1502 while only 3 (12.0%) of the lamotrigine-tolerant controls tested positive for this allele. 

• The risk of lamotrigine-induced SJS/TEN was significantly higher in patients with HLA-B*1502, with an odds ratio (OR) of 4.74 [95% confidence interval (CI) 1.14-19.73, p = 0.032]. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of HLA-B*1502 for lamotrigine-induced SJS/TEN was 39.29%, 88.00%, 78.57% and 56.41%, respectively. The HLA-B*1502 allele was present in 2 (25.0%) of phenytoin-induced SJS/TEN cases and 5 (41.7%) of the phenytoin-tolerant controls tested positive for HLA-B*1502 allele. 

• The risk of phenytoin-induced SJS/TEN was not higher in the patients with HLA-B*1502 (OR = 0.467 [95% confidence interval (CI) 0.065-3.34, p = 0.642]). Lamotrigine-induced SJS/TEN is associated with HLA-B*1502 allele in an Iranian population but this is not the case for phenytoin-induced SJS/TEN.

 Kwan, 2014

https://pubmed.ncbi.nlm.nih.gov/25647819/

• Introduction
  The presence of HLA-B*15:02 allele greatly increases the risk of carbamazepine-induced severe cutaneous adverse drug reactions, namely Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). 1,2 It is unknown whether HLA-B*15:02 also confers increased risk of SJS/TEN induced by
  other anti-epileptic drugs (AEDs). 

• HLA-B*15:02 in single cases of SJS/TEN is reported to be induced by phenytoin and lamotrigine. 1,3 This study examined the association between HLA-B*15:02 allele and SJS/TEN induced by different AEDs.
• 
  Methods
  This case-control study was conducted from March 2010 to September 2011. Ethics approval was obtained from five Hospital Authority clusters. Written informed consent was obtained from each patient. Medical records of 25 male and 30 female Han Chinese patients aged 10 to 85 (mean, 44.1; standard deviation [SD], 17.1) years who presented with SJS/
  TEN from 1 January 1993 to 30 June 2009 within 12 weeks after commencing AEDs of carbamazepine
  (n=27), phenytoin (n=15), valproate (n=3),
  phenobarbital (n=2), lamotrigine (n=6), gabapentin (n=1), and levetiracetam (n=1) were reviewed using the Clinical Data Analysis and Reporting System. From a DNA bank of over 1800 Han Chinese epilepsy patients, 275 controls aged 10 to 90 (mean, 44.1; SD, 16.9) years who were tolerant to AEDs after
  taking them for at least 3 months without developing skin rash were identified. Cases and controls were matched in age and AED prescribed in the ratio of 1:5. Hong Kong Med J 2014;20(Suppl 7):S16-8 HHSRF project number: 07080381 PKL Kwan *, MHL Ng, SV Lo
  DNA collected from blood and saliva samples
  were extracted using QIAamp DNA kit (Qiagen,
  Hilden, Germany) and Oragene DNA Self-Collection Kit (DNA Genotek, Ottawa, Canada), respectively. HLA-B*15:02 was detected by sequence-based typing. In brief, polymerase chain reaction was performed with primers spanning exon 2 to 3 of the HLA-B region. DNA sequencing was performed using ABI 3730xl DNA sequencer (Applied Biosystems, Foster City [CA], USA) and the resulting sequences were analysed using SBTengine (GenDx,
  Utrecht, The Netherlands).
• 
  Based on estimation from previous results, 1 the
  combined frequency of HLA-B*15:02 was assumed to be 15% in controls and 49% in cases. The sample size would have 90% power to detect a difference in frequency between cases and controls at P=0.001. Pearson Chi-square test or Fisher’s exact test was
  used to compare the frequencies of HLA-B*15:02 between cases and controls. To account for multiple comparisons, a P value of <0.001 after Bonferroni correction was considered statistically significant.
• 
  Results
  There was sample error in one case and one
  control, and thus only 54 cases and 274 controls
  were analyzed. HLA-B*15:02 was associated with AED-induced SJS/TEN (63.0% of cases vs 15.3% of controls; P=3.38  ́ 10 -14 ; odd ratios [OR]=9.39; 95% confidence interval [CI], 4.94-17.86; Table). Specifically, HLA-B*15:02 was associated with carbamazepine-induced SJS/TEN (92.3% [24/26] of cases vs 11.9% [16/135] of controls; P=3.51  ́ 10 -18 ; OR=89.25; 95% CI, 19.25-413.83). 
• HLA-B*15:02 was also found in 46.7% (7/15) of phenytoin-induced HEALTH AND HEALTH SERVICES RESEARCH FUND 1 PKL Kwan *, 2 MHL Ng, 3 SV Lo 1 Department of Medicine and Therapeutics, The Chinese University of
  Hong Kong, Prince of Wales Hospital
  2 Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital 3 Division of Planning & Strategy, Hospital Authority Head Office, Hong Kong
  

https://pubmed.ncbi.nlm.nih.gov/36183454/

• Purpose: Antiepileptic drugs (AEDs) are extensively used to manage epilepsy and other comorbidities associated with seizures. Human Leukocyte Antigen (HLA) has a strong association with AED-induced severe cutaneous adverse drug reactions.

• Objective: We aimed to perform a systematic review and meta-analysis to identify, critically evaluate, and synthesize the best possible evidence on HLA-associated AED-induced Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN).

• Methods: MEDLINE/PubMed, Scopus, and the Cochrane Library were searched for literature from inception up to July 2022. We included case control studies analyzing association between HLA and AED-induced SJS/TEN. We assessed the studies' risk of bias in using Quality of genetic studies (Q-genie) tool. Outcomes focused on association (risk) between HLA and AED-induced SJS/TEN. The estimated risk was presented in the form of odds ratio (OR).

• Results: We included 37 studies (51,422 participants; 7027 cases and 44,395 controls). There was a significantly higher risk of Carbamazepine-induced SJS/TEN with HLA-A (OR: 1.50; 95% CI: 1.03 to 2.17), HLA-B (OR: 1.94; 95% CI: 1.45 to 2.58), HLA-C (OR: 7.83; 95% CI: 4.72 to 12.98), and HLA-DRB1 (OR: 2.82; 95% CI: 1.94 to 4.12). Lamotrigine-induced SJS/TEN posed a higher risk with HLA-A (OR: 2.38; 95% CI: 1.26 to 4.46) and HLA-B (OR: 2.79; 95% CI: 1.75 to 4.46). Phenytoin-induced SJS/TEN showed a higher risk with HLA-A (OR: 3.47; 95% CI: 2.17 to 5.56), HLA-B (OR: 1.72; 95% CI: 1.38 to 2.15), and HLA-C (OR: 2.92; 95% CI: 1.77 to 4.83). 

• Phenobarbital-induced SJS/TEN had a higher risk with HLA-A (OR: 6.98; 95% CI: 1.81 to 26.84), HLA-B (OR: 2.40; 95% CI: 1.39 to 4.17), and HLA-C (OR: 3.37; 95% CI: 1.03 to 11.01). Zonisamide-induced SJS/TEN was significantly associated with HLA-A*02:07 (OR: 9.77; 95% CI: 3.07 to 31.1), HLA-B*46:01 (OR: 6.73; 95% CI: 2.12 to 21.36), and HLA-DRB1×08:03 (OR: 3.78; 95% CI: 1.20 to 11.97). All other alleles of HLA were observed to have a non-significant association with AED-induced SJS/TEN. All included studies were of good quality, with a score of >50 and a mean score of 54.96 out of 77.

• Conclusion: Our study showed a significant association between few variants of HLA alleles and AED-induced SJS/TEN. Evidences from our study could help in population-based studies and in implementation of individualized treatment regimens. These findings could be part of translational research helping in precision therapy.

 Li, 2020

https://pubmed.ncbi.nlm.nih.gov/33350798/  

• Background: Several studies demonstrated a connection between human leukocyte antigen (HLA)-B∗1502 and lamotrigine (LTG)-induced cutaneous adverse drug reactions (cADRs). The correlation between the HLA-A∗24:02 and LTG-cADRs remains controversial. 

• To examine the associations between HLA-A∗24:02 and LTG-cADRs, we conducted a systematic review and meta-analysis.

• Methods: We performed a comprehensive search of the literature in several electronic database systems including Cochrane Library, EMBASE and PubMed from inception to January 2020. Review Manager was used to compare the frequencies of HLA-A∗24:02 carriers between the subgroups.

• Results: A total of 5 studies were eligible, including 197 LTD-cADRs, 396 LTD-tolerant controls, and 2068 population controls. 

• Compared with the LTG-tolerant controls, there was a statistically significant association between the HLA-A∗24:02 allele and LTG-induced cADRs (odds ratios: 1.94, 95% confidence intervals 1.06-3.54; P = .03). 

• Compared with the general population, the relationship between the HLA-A∗24:02 genotype and LTG-induced cADRs was statistically significant (summary odds ratios: 2.12, 95% confidence intervals 1.04-4.30; P = .04).

• Conclusions: HLA-A∗24:02 may be a risk factor for LTG-cADRs.

Sukasem, 2020

https://pubmed.ncbi.nlm.nih.gov/32452529/

• Co-trimoxazole (CTX) causes various forms of severe cutaneous adverse reactions (SCARs). This case-control study was conducted to investigate the involvement between genetic variants of human leukocyte antigen (HLA) and CYP2C9 in CTX-induced SCARs, including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) in Thai patients. 

• Thirty cases of CTX-induced SCARs were enrolled and compared with 91 CTX-tolerant controls and 150 people from the general Thai population. Cases comprised 18 SJS/TEN and 12 DRESS patients. This study demonstrated that genetic association of CTX-induced SCARs was phenotype-specific. HLA-B*15:02 and HLA-C*08:01 alleles were significantly associated with CTX-induced SJS/TEN, whereas the HLA-B*13:01 allele was significantly associated with CTX-induced DRESS. 

• In addition, a significant higher frequency of HLA-A*11:01-B*15:02 and HLA-B*13:01-C*03:04 haplotypes were detected in the group of CTX-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and DRESS cases, respectively. Genetic association of CTX-induced SCARs is phenotype-specific. Interestingly, these association was observed only in HIV-infected patients but not in non-HIV-infected patients.

Wang, 2011

https://pubmed.ncbi.nlm.nih.gov/21878835/

• Objectives: N-acetyltransferase 1 (NAT1) metabolizes drugs and environmental carcinogens. NAT1 alleles *10 and *11 have been proposed to alter protein level or enzyme activity compared with wild-type NAT1 *4 and to confer cancer risk, through uncertain pathways. This study characterizes regulatory polymorphisms and underlying mechanisms of NAT1 expression.

• Methods: We measured allelic NAT1 mRNA expression and translation, as a function of multiple transcription start sites, alternative splicing, and three 3'-polyadenylation sites in human livers (one of which was discovered in this study), B lymphocytes, and transfected cells. In a clinical study of 469 patients with HIV/AIDS treated with the NAT1/NAT2 substrate sulfamethoxazole (SMX), associations were tested between SMX-induced hypersensitivity and NAT1 *10 and *11 genotypes, together with known NAT2 polymorphisms.

• Results: NAT1 *10 and *11 were determined to act as common regulatory alleles accounting for most NAT1 expression variability, both leading to increased translation into active protein. NAT1 *11 (2.4% minor allele frequency) affected 3'-polyadenylation site usage, thereby increasing formation of NAT1 mRNA with intermediate length 3'-untranslated region (major isoform) at the expense of the short isoform, resulting in more efficient protein translation. 

• NAT1 *10 (19% minor allele frequency) increased translation efficiency without affecting 3'-untranslated region polyadenylation site usage. Livers and B-lymphocytes with *11/*4 and *10/*10 genotypes displayed higher NAT1 immunoreactivity and NAT1 enzyme activity than the reference genotype *4/*4. Patients who carry *10/*10 and *11/*4 (fast NAT1 acetylators) were less likely to develop hypersensitivity to SMX, but this was observed only in individuals who are also carrying a slow NAT2 acetylator genotype.

• Conclusion: NAT1 *10 and *11 significantly increase NAT1 protein level/enzyme activity, enabling the classification of carriers into reference and rapid acetylators. Rapid NAT1 acetylator status seems to protect against SMX toxicity by compensating for slow NAT2 acetylator status.

Jantararoungtong, 2021

https://pubmed.ncbi.nlm.nih.gov/34148467/

• Introduction: Pharmacogenomics has great potential in reducing drug-induced severe cutaneous adverse drug reactions (SCARs). Pharmacogenomic studies have revealed an association between HLA genes and SCARs including acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).

• Areas covered: Pharmacogenomics-guided therapy could prevent severe drug hypersensitivity reactions. The US Food and Drug Administration (FDA), Clinical Pharmacogenetics Implementation Consortium (CPIC), and Dutch Pharmacogenetics Working Group (DPWG) provided guidelines in the translation of clinically relevant and evidence-based SCARs pharmacogenomics research into clinical practice. In this review, we intended to summarize the significant HLA alleles associated with SCARs induced by different drugs in different populations. We also summarize the SCARs associated with genetic and non-genetic factors and the cost-effectiveness of screening tests.

• Expert opinion: The effectiveness of HLA screening on a wider scale in clinical practice requires significant resources, including state-of-the-art laboratory; multidisciplinary team approach and health care provider education and engagement; clinical decision support alert system via electronic medical record (EMR); laboratory standards and quality assurance; evidence of cost-effectiveness; and cost of pharmacogenomics tests and reimbursement.

 Asyraf, 2022

https://pubmed.ncbi.nlm.nih.gov/35903308/ 

• Drug hypersensitivity is an inflammatory or immune reaction induced by drugs. It can be fatal if not appropriately treated and cause the risk of long-term complications. Sulfonamides are classified as antimicrobial drugs with a broad spectrum effective for gram-positive and gram-negative bacteria. This antibacterial agent works by competitively inhibiting folic acid synthesis, which prevents the growth and proliferation of microorganisms. In its use as antibiotics, sulfonamides can also cause adverse reactions in specific individuals. It has been widely reported that sulfonamide antimicrobials cause hypersensitivity reactions mediated by IgE or T cells. 

• This review identifies symptoms or signs that can appear, as well as genes associated with sulfonamide hypersensitivity reactions, as sulfonamide may cause hypersensitivity in the form of uveitis, skin rash, Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), parotitis, angioedema, drug reaction with eosinophilia and systemic symptoms (DRESS), and pruritus. 

• In addition, several genes were found to be associated with sulfonamide hypersensitivity, including HLA-A29, HLA-B12, HLA-DR7, HLA-B44, and HLA A*11:01.